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Blood, Vol. 93 No. 10 (May 15), 1999:
pp. 3558-3564
Prevention of Graft-Versus-Host Disease by Induction of Immune
Tolerance With Ultraviolet B-Irradiated Leukocytes in H-2 Disparate
Bone Marrow Donor
M.L.U. del Rosario,
James R. Zucali, and
K.J. Kao
From the University of Florida Departments of Pediatrics, Medicine,
and Pathology, Immunology & Laboratory Medicine, Gainesville, FL.
Transfusions (Tx) of Ultraviolet B (UVB)-irradiated peripheral blood
mononuclear leukocytes (MNL) have been shown to induce humoral immune
tolerance to major histocompatability complex (MHC) antigens
(Blood 88:4375, 1996). To determine whether cellular immune
tolerance to MHC antigens can be induced by the same approach, transplantation of bone marrow and spleen cells from tolerant donors
across the H-2 barrier was conducted to study its effect on prevention
of graft-versus-host disease (GVHD). After immune tolerance induction
by four weekly Tx of UVB-irradiated BALB/c (H-2d)
peripheral blood MNL into CBA/HT6 (H-2k) mice, bone marrow
cells (BMC) and spleen MNL from tolerant or naive CBA mice were
transplanted into lethally irradiated BALB/c mice. The transplanted
mice were followed by measuring body weight, peripheral leukocyte
counts, GVHD, survival, and cytokine response. All BALB/c recipient
mice were fully engrafted with H-2k CBA donor cells after
transplantation. The severity of GVHD was significantly attenuated in
BALB/c mice transplanted with BMC and spleen MNL from tolerant CBA
donor mice. The recovery of peripheral leukocyte and lymphocyte counts
were faster and more complete in mice transplanted with cells from the
tolerant donors. The serum cytokine profile after transplantation with
tolerant donor cells showed increased interleukin-4 and reduced gamma
interferon that are consistent with a polarized Th2 response. The
results pooled from three separate experiments showed that BALB/c mice transplanted with 5 × 106 BMC and 4 × 105
spleen MNL from tolerant CBA donors had better overall survival than
the control group (72% v 17%, P = .018). The
findings show that transplantation with bone marrow and spleen cells
from tolerant H-2 disparate donor mice is associated with significant
attenuation of GVHD and better outcomes. The results also support that
transfusions of UVB-irradiated leukocytes may induce cellular
immune tolerance.
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